1. Frontline Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Shows Superior Efficacy in Comparison to Bendamustine (B) and Rituximab (BR) in Previously Untreated and Physically Fit Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Final Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10-Study) Eichhorst B et al. Proc ASH 2014;Abstract 19.

2. Background Fludarabine/cyclophosphamide/rituximab (FCR) is the standard front-line treatment regimen for physically fit patients with advanced chronic lymphocytic leukemia (CLL) with low comorbidity burden. –The addition of rituximab to fludarabine/cyclophosphamide (FC) in the CLL8 trial led to prolongation of progression-free (PFS) and overall survival (OS) as first-line treatment for physically fit patients with CLL (Leuk Lymphoma 2013;54:1821). –However, the FCR regimen was associated with a high rate of severe infections and higher rates of secondary neoplasias compared to FC. Study objective: To evaluate the efficacy and tolerability of FCR in comparison to bendamustine/rituximab (BR) as front- line therapy for fit patients with CLL without del(17p). Eichhorst B et al. Proc ASH 2014;Abstract 19.

3. CLL10: Final Analysis of a Phase III Trial of FCR versus BR in Advanced CLL FCR (n = 284) Fludarabine 25 mg/m 2 IV days 1-3 Cyclophosphamide 250 mg/m 2 IV days 1-3 Rituximab 375 mg/m 2 IV day 0, cycle 1 Rituximab 500 mg/m 2 IV day 1, cycles 2-6 BR (n = 280) Bendamustine 90 mg/m 2 IV days 1-2 Rituximab 375 mg/m 2 day 0, cycle 1 Rituximab 500 mg/m 2 IV day 1, cycles 2-6 Primary endpoint: Noninferiority of BR vs FCR for PFS (hazard ratio BR/FCR < 1.388) Eligibility (n = 564) Untreated, active CLL without del(17p) Good physical fitness (CIRS ≤6, creatinine clearance ≥70 mL/min) R Eichhorst B et al. Proc ASH 2014;Abstract 19. CIRS = Cumulative Illness Rating Scale

4. Patient Characteristics Characteristics FCR (n = 282) BR (n = 279) Median age61.0 years62.1 years Age > 6530.5%38.7% Male71.3%74.2% Median time since diagnosis21.6 months24.6 months ECOG PS = 064.1% CIRS22 Mean number of cycles5.275.41 Eichhorst B et al. Proc ASH 2014;Abstract 19.

5. Progression-Free Survival (PFS) With permission from Eichhorst B et al. Proc ASH 2014;Abstract 19. Cumulative Survival Median PFS FCR: 55.2 months BR: 41.7 months HR: 1.626 p < 0.001

6. PFS in IGHV Matched Population HR: 1.565 P < 0.005 With permission from Eichhorst B et al. Proc ASH 2014;Abstract 19. Median PFS FCR: Not reached BR: 43.1 months Cumulative Survival

7. PFS by IGHV Status With permission from Eichhorst B et al. Proc ASH 2014;Abstract 19. 1.0 0.8 0.6 0.4 0.2 0 Unmutated IGHV: p = 0.017 FCR: 42.7 mo; BR: 33.6 mo Mutated IGHV: p = 0.153 FCR: NR; BR: 52 mo Cumulative Survival 01224364860 Mos to Event (PFS) 01224364860 Mos to Event (PFS) 1.0 0.8 0.6 0.4 0.2 0 Cumulative Survival FCR BR FCR

8. Response FCR (n = 282) BR (n = 279)p-value Overall response rate95.4%95.7%1.0 Complete response (CR + CRi) 39.7%30.8%0.034 Complete response (CR)35.1%30.4%NR CR with incomplete marrow recovery (CRi) 4.6%0.4%NR Partial response (PR)55.7%64.9%NR Stable disease/progressive disease 2.2% NR NR = not reported Eichhorst B et al. Proc ASH 2014;Abstract 19.

9. Minimal Residual Disease (MRD) MRD negativity (intent to treat) FCR (n = 282) BR (n = 279) BM at FR26.6%11.1% PB at FR48.6%38.4% PB 12 months after FR19.7%9.0% PB 18 months after FR18.0%8.5% MRD negativity (evaluable patients) FCRBR PB at FR (n = 185, 170)74.1%62.9% PB 18 months after FR (n = 65, 65)53.8%24.6% BM = bone marrow; FR = final restaging; PB = peripheral blood Eichhorst B et al. Proc ASH 2014;Abstract 19.

10. Select Adverse Events Adverse event FCR (n = 279)BR (n = 278)p-value Neutropenia84.2%59.0%<0.001 Anemia13.6%10.4%0.20 Thrombocytopenia21.5%14.4%0.03 Infection39.1%26.8%<0.001 During therapy (tx) only22.6%17.3%0.1 During first 5 mo after tx11.8%3.6%<0.001 In patients ≤65 years35.2%27.5%0.1 In patients >65 years47.7%20.6%<0.001 Secondary neoplasm*6.1%3.6%0.244 * sAML/MDS: FCR (n = 6); BR (n = 1) Eichhorst B et al. Proc ASH 2014;Abstract 19.

11. Author Conclusions Final analysis of the Phase III CLL10 study demonstrated inferiority of BR to FCR with regard to PFS and complete response rate. BR is associated with lower rates of neutropenias and severe infections in elderly patients. FCR remains standard therapy for fit patients. BR may be considered for fit elderly patients as an alternative. Eichhorst B et al. Proc ASH 2014;Abstract 19.

12. Investigator Commentary: CLL10 — Efficacy and Tolerance of FCR in Comparison with BR as Front-Line Therapy for Fit Patients with CLL without Del(17p) The preliminary results of this large Phase III study with relatively young patients were presented at ASH last year, but these are the final data that demonstrate a higher complete response rate for patients who received FCR. Perhaps more importantly, the rate of MRD with FCR was 74% compared to 62% with BR. With 18 months of follow-up, 53% of patients who received FCR remained MRD-negative compared to only 24% with BR. Obviously, toxicity was a little higher with FCR. What these results mean for the practicing oncologist is that we have choices. Both regimens are active. If you have a young, fit patient without a lot of contraindications to treatment, that patient's best chance at a prolonged disease-free interval using chemoimmunotherapy is with FCR. But if you have any hesitation about tolerance or the patient is older, BR is an acceptable alternative. Interview with Jonathan W Friedberg, MD, MMSc, January 8, 2015